Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. In particular, compounds in the folic acid family have various activities at the enzymatic level as they inhibit such enzymes as dehydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthetase.
Recently a series of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives have been disclosed, for example in European publication No. 0434426, and shown to be particularly useful antifolate drugs. Among these 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives is pemetrexed disodium heptahydrate of formula I.
Pemetrexed disodium heptahydrate is a multitargeted antifolate drug approved for treatment of mesothelioma and for second-line treatment of non small cell lung cancer.
Pemetrexed disodium salt heptahydrate is marketed by Eli Lilly and Company under the trade name ALIMTA® as a sterile lyophilized powder for intravenous administration. This member of the folic acid family has been approved for treatment of malignant pleural mesothelioma and for second-line treatment of non small cell lung cancer. See Physicians' Desk Reference, 60th ed., pp. 1722-1728 (2006). The commercial product is reported to be a lyophilized powder of heptahydrate pemetrexed disodium and mannitol.
European publication No. 0432677 reports one of the first syntheses of pemetrexed disodium heptahydrate. This route of synthesis, however, is not very suitable for industrial production due to the number of steps and the poor overall yield.
More recent syntheses of pemetrexed disodium heptahydrate (e.g. U.S. Pat. No. 5,416,211) follow a different route through 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid of formula II.

The compound of formula II may be prepared via an intermediate of formula III,
where R is hydrogen or a carboxy protecting group.
U.S. Pat. No. 5,416,211 (“'211 patent”) and U.S. Pat. No. 6,262,262 (“'262 patent”) disclose the preparation of the compound of formula II by halogenation of the intermediate of formula III to provide the following halo intermediate,
which is not isolated. The halo intermediate is then condensed in-situ with a pyrimidine moiety to form an ester of the following formula IV.

The ester of formula IV is then hydrolyzed to form the compound of formula II. The process is shown in the following scheme I.

However, the '262 patent reports that the aldehyde intermediate of formula III is obtained with unspecified byproducts, is scarcely stable and tends to decompose during purification. Thus, the '262 patent discloses an additional process wherein the intermediate of formula III is prepared and then transformed into a sulfonic acid metal cation salt of formula V,
which can be isolated and purified. The intermediate of formula III is then re-generated from sulfonic acid metal cation salt of formula V, transformed in situ into the corresponding alpha-halo derivative and treated with 2,4-diamino-6-hydroxy pyrimidine without isolation of the intermediate to obtain the ester of formula IV. The preparation of compound of formula II via the sulfonic acid metal cation salt of formula V is illustrated by the following scheme II.

Another process is disclosed in C. J. Barnett, et al., “A Practical Synthesis of Multitargeted Antifolate LY231514,” Organic Process Research & Development, 3(3): 184-188 (1999) and is illustrated by the following scheme III.

Compound 9 is obtained by coupling methyl 4-bromobenzoate and 3-butyn-1-ol in the presence of a Palladium catalyst (Heck reaction), followed by catalytically reducing the obtained alkyne with H2 on Pd/C (a pyrophoric agent). The reduced alkyne of formula 7 is then oxidized with NaOCl and a 2,2,6,6-tetramethylpiperidinyloxy (“TEMPO”) catalyst, followed by brominating with 3,5-di-tert-butyl-4-hydroxy benzyl acrylate (“DBBA”) and HBr to obtain compound 9. Then compound 9 is transformed to compound II by the same condensation as described above.
Accordingly, there is a need for a concise process for preparing the pemetrexed intermediate of formula II.